Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Li B, Senbabaoglu Y, Peng W, Yang ML, Xu J, Li JZ. Genomic estimates of aneurploid content in glioblastoma multiforme and improved classification. Clin Can Res 2012;18:5595–605.Several schemes have been described regarding transcriptomal subtypes for glioblastoma (GBM). While some similarities exist among the classification patterns, additional study is needed to determine if a standardized classification schema is to be developed. The authors studied data from the Cancer Genome Atlas (TCGA), including both transcriptomal data and methylation profiling data. In addition, they used allele-specific copy number data to estimate the aneuploid content of each tumor and incorporated this measure to estimate the proportion of non-neoplastic tissue within the tumor sample. TCGA required a pathologist assessment that the tumor nuclei comprise at least 80% of the sample. Interestingly, the authors found that aneuploid estimates based on SNP data were only moderately correlated with pathologists' report of percent tumor cells. Among the transcriptomal subclasses that are most frequently recognized are the proneural and mesenchymal subclasses. The authors noted a tight cluster of tumors that narrowed proneural tumors into only a small proportion of samples and showed that these were generally positive for the CpG island methylator phenotype (CIMP) that had been previously described as comprising a subset of proneural tumors. Unexpectedly, they identified a tight correlation between aneuploid content and transcriptomal class, with mesenchymal GBMs having higher aneuploid content. They used publicly available data to implicate the non-neoplastic content as macrophage/microglial cells, which appear at increased levels in mesenchymal tumors. Finally, their system resulted in a reclassification of TCGA samples and a revision of the schema to include a proliferative subtype, and advocated elimination of a previously described neural subtype. With respect to patient outcome, they found that, as expected, the G-CIMP-positive/proneural group had an improved outcome overall compared to the other 3 groups. However, among the nonproneural groups, additional significant differences in patient outcome were observed based on their new classification scheme. This finding was validated in an independent patient cohort. Overall, the authors incorporate aneuploid content and methylation profiling data to revise the classification scheme of GBM into subtypes with novel clinical implications. This methodology may serve to better understand the biology and clinical behavior of patients with GBM.Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, et al. The Requirement for Cyclin D Function in Tumor Maintenance. Cancer Cell 2012;22:438–51.Several oncogenic signaling pathways converge on the activity of D cyclins, key components of the cell cycle machinery that bind and activate cyclin-dependent kinases (CDK). Genomic alteration of cyclin D genes has been found in a large proportion of human cancers. Cyclins D1, D2, and D3 display high sequence homology, and loss of individual cyclins are dispensable for normal organ development. However, specific D cyclins are critical for the etiology of distinct tumor types, such as breast (cyclin D1) and lymphoma (cyclin D3). An outstanding question is whether this family of proteins plays a role in tumor maintenance and progression. In this manuscript, Choi and colleagues generated a mouse model for breast cancer in which cyclin D1 expression is ablated in an inducible manner. Using this novel genetic tool, the authors found that cyclin D1 (Ccnd1) ablation led to decreased tumor growth, tumor size, and proliferation of cancer cells in vivo. Additionally, loss of function of cyclin D1 triggered a senescence phenotype. The authors used a complementary pharmacologic approach to determine that treating a mouse model for breast cancer with PD 0332991, a potent CDK inhibitor, produced the same outcomes (i.e., cancer cell senescence and decreased tumor burden) as induction of cyclin D1 ablation. Choi and colleagues carried out similar genetic and pharmacologic experiments to determine the role of cyclin D3 (Ccnd3) in T-cell acute lymphoblastic leukemia (T-ALL) maintenance. Specifically, hematopoietic progenitor cells (HPC) from a Notch1-activated T-ALL mouse model harboring an inducible deletion of cyclin D3 were transplanted into the bloodstream of recipient mice. Upon development of T-ALL, these mice were treated with polyI-polyC (pI-pC) to induce cyclin D3 ablation, which led to a reduction in the number of cancer cells in the peripheral blood and significantly prolonged survival. FACS and TUNEL staining experiments revealed that cyclin D3 was critical to maintain T-ALL cell numbers. In addition, ablation of cyclin D3 triggered programmed cell death and the disappearance of T-ALL cells in vivo. Similarly, treatment with PD 0332991 inhibited cell cycle progression and induced apoptosis of leukemic cells in T-ALL mice, resulting in decreased cancer cell counts in the peripheral blood, reduction in tumor cell infiltration, and improved survival. The authors analyzed the function of cyclin D-CDK interactions in a panel of human leukemia cell lines and found that treatment with PD 0332991 led to cell cycle arrest and induction of apoptosis only in the subset of samples harboring Notch1 activating mutations. They extended their findings to an in vivo context by xenografting human T-ALL cell lines, designed to express the bioluminescent reporter firefly luciferase, into recipient mice. Similar to the authors' in vitro findings, their bioluminescent experiments showed that mice treated with PD 0332991 displayed a dramatic reduction in tumor burden as well as increased T-ALL cell apoptosis compared with vehicle-treated mice. Microarray analyses of human T-ALL and mouse breast cancer cells treated with the CDK inhibitor PD 0332991 uncovered three functionally distinct nodes of gene expression. A cohort of genes involved in cell cycle function was downregulated upon PD 0332991 administration in both T-ALL and breast cancer cell lines. A group of apoptosis-related genes was differentially regulated in only T-ALL cells, and microarray analysis of breast cancer cells revealed enrichment in genes associated with cell division and cell senescence. These results suggest that CDK inhibition triggers a transcriptional cell death program, leading to tumor cell apoptosis. Interestingly, induced acute ablation of cyclin D1 or D3 in adult disease-free mice had very minor or no health impact, which suggests that targeting distinct D cyclins to specifically kill cancer cells without affecting normal cells may represent a novel and effective therapeutic window.He Y, Zha J, Wang Y, Liu W, Yang X, Yu P. Tissue damage-associated ‘danger signals’ influence T cell responses that promote the progression of pre-neoplasia to cancer. Cancer Res;2704.2012; Published OnlineFirst October 29, 2012; doi:10.1158/0008-5472.CAN-12-2704.The mechanism(s) that mediates immune evasion by tumors remain an enigma. Recent studies are now providing relevant insights into the role of molecules referred to as damage-associated molecular patterns (DAMP) to elicit a danger signal in response to tissue damage. The DNA-binding protein, high mobility group box 1 (HMGB1) protein, is a well-studied DAMP. Elevated expression and serum levels of HMGB1 have been linked to cancer invasion and metastasis. However, a functional link between HMGB1 and T cell activation by cancers has not been established. In this study, He and colleagues studied the well- established transgenic adenocarcinoma mouse prostate (TRAMP) and TRAMP/RAG mice (a cross of TRAMP and Rag1−/− mice lacking all T and B cells) and surprisingly found that tumor progression was significantly reduced in TRAMP/RAG mice as compared with the TRAMP mice growing in the presence of lymphocytes. Reconstitution experiments of the TRAMP/RAG mice with lymphocytes from TRAMP mice resulted in significantly elevated tumor progression, clearly indicating a definitive role of the lymphocytes in tumor promotion. It was shown that release of HMGB1 into the tumor microenvironment stimulated antigen- specific T cells. The tumor-infiltrating T cells expressed high levels of lymphotoxins and promoted tumor progression by recruiting macrophages through an LTβR-dependent pathway. Blocking HMGB1 markedly reduced tumor progression by decreasing T cell-derived lymphotoxins and macrophage infiltration. This study uncovers a novel role of the DAMP-associated molecule HMBG1 on T cell activation leading to tumor progression. Continuous identification of such molecules and associated pathways will assist in developing novel methods for cancer therapeutics and prognosis.Liao X, Lochhead P, Nishihara R, Morikawa, T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367:1596–606.Aspirin taken daily seems to reduce the development and spread of several important human cancers, especially of the colon and rectum. However, aspirin can cause gastric bleeding, and no reliable biomarker identifies cancer types or subtypes that may benefit from aspirin in a preventative or adjuvant (i.e., after diagnosis) capacity. A study published on October 25, 2012, in the New England Journal of Medicine suggests that mutations in PIK3CA could provide a biomarker for adjuvant aspirin in patients with a diagnosis of colorectal cancer (CRC). Aspirin inhibits prostaglandin-endoperoixide synthase 2 (PTGS2; otherwise known as COX2) and this decreases PIK3CA activity that is important for malignant cell survival. Liao and colleagues conducted a molecular pathology epidemiology study to investigate the hypothesis that activating mutations of PIK3CA may influence the actions of aspirin in patients with CRC. They identified 964 CRC patients from the many thousands who took part in the US-wide Nurses Health Study and Health Professionals Follow-up Study and extracted DNA from archived paraffin embedded biopsies. As expected, 17% of tumors had a PIK3CA mutation. Aspirin taken after diagnosis significantly increased five-year survival in these patients but had no impact in patients whose tumors had wild-type PIK3CA. Whether the mechanism of action of aspirin in patients with PIK3CA mutations involved a decrease in malignant cell survival could not be proved by this retrospective study, and the authors point out that the finding needs to be replicated in another patient cohort. However, if a simple test could tell whether aspirin would be beneficial as an adjuvant treatment after diagnosis of CRC or other cancers with mutated PIK3CA, this would be a major public health advance, increasing survival of 10-20% of CRC patients after diagnosis with a simple and inexpensive drug.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.